The present invention relates to compounds which modulate binding of immunoglobulins to Fc receptors and uses thereof.
Fc receptors (FcR) are a family of highly related receptors that are specific for the Fc portion of immunoglobulin (Ig). These receptors have major roles in normal immunity and resistance to infection and provide the humoral immune system with a cellular effector arm. Receptors have been defined for each of the immunoglobulin classes and as such are defined by the class of Ig of which they bind (i.e. Fc gamma receptor (Fcxcex3R) bind gamma immunoglobulin (IgG), Fc epsilon receptor (Fcxcex3R) bind epsilon immunoglobulin (IgE), Fc alpha receptor (Fcxcex1R) bind alpha immunoglobulin (IgA)). Among the Fcxcex3R receptors, three subfamily members have been defined; Fcxcex3RI, which is a high affinity receptor for IgG; Fcxcex3RII, which are low affinity receptors for IgG that avidly bind to aggregates of immune complexes; and Fcxcex3RIII, which are low affinity receptors that bind to immune complexes. These receptors are highly related structurally but perform different functions. The structure and function of Fcxcex3RII is of interest because of its interaction with immune complexes and its association with disease.
Fcxcex3R are expressed on most hematopoietic cells, and through the binding of IgG play a key role in homeostasis of the immune system and host protection against infection. Fcxcex3RII is a low affinity receptor for IgG that essentially binds only to IgG immune complexes and is expressed on a variety of cell types including, for example monocytes, macrophages, neutrophils, eosinophils, platelets and B lymphocytes. Fcxcex3RII is involved in various immune and inflammatory responses including antibody-dependent cell-mediated cytotoxicity, clearance of immune complexes, release of inflammatory mediators and regulation of antibody production. The binding of IgG to a Fcxcex3R can lead to disease indications that involve regulation by Fcxcex3R. For example, the autoimmune disease thrombocytopenia purpura involves tissue (platelet) damage resulting from Fcxcex3R-dependent IgG immune complex activation of platelets or their destruction by Fcxcex3R+ phagocytes. In addition, various inflammatory diseases are known to involve IgG immune complexes (e.g. rheumatoid arthritis, systemic lupus erythematosus), including type II and type III hypersensitivity reactions. Type II and type III hypersensitivity reactions are mediated by IgG, which can activate either complement-mediated or phagocytic effector mechanisms, leading to tissue damage.
Because FcR are involved in a variety of biological mechanisms, there is a need for compounds which affect the binding of immunoglobulins to FcR. There is also a need for using such compounds to treat a variety of illnesses.
The present invention provides a pharmaceutical composition comprising:
(a) a compound selected from the group consisting of an aromatic compound of the formula: 
a heteroaromatic compound of the formula: 
a cyclic compound of the formula: 
a bicyclic compound of the formula: 
and an amino acid derivative of the formula: 
or salts thereof,
wherein
each of W1 and W2 is independently CO2R15, C(xe2x95x90NH)NH(OH), SO3R15, C(xe2x95x90NH)NH2, OPO(OR15)2, C(xe2x95x90O)CF3 or PO(OR15)2;
each of Ar1, Ar2, Ar4 and Ar5 is independently C6-C20 aryl or C1-C20 heteroaryl;
Ar3 is C1-C20 heteroaryl;
each of X1, X2, X3, X4, X5, X6, X7 and X8 is independently methylene, O, S or NR16;
each of R1 and R2 is independently a bond, C1-C6 alkylene, or halogenated C1-C6 alkylene;
each of R3 and R4 are independently halogen, xe2x80x94Z1 or C1-C6 alkyl;
each of X9, Y1 and Z1 is independently OR17, SR17 or NR17R18;
each of R5 and R6 is independently amino acid side chain residue or a moiety of the formula xe2x80x94R19xe2x80x94W3;
each of R8, R9 and R11 is independently an amino acid side chain residue, provided R11 is not H or CH3;
R7 is OR20, NR21R22, or from about 1 to about 10 amino acids;
R10 is C1-C6 alkylene;
R12 is C1-C6 alkyl or C6-C20 aralkyl;
W3 is C(xe2x95x90O)X10;
X10 is OR23 or NR24R25;
each of R13, R15, R17, R18, R20, R21, R23 and R24 is independently hydrogen or C1-C6 alkyl;
each R16 is independently H, C6-C20 aryl or an amide protecting group;
R19 is C1-C6 alkylene;
each of R22 and R25 is independently H, C1-C6 alkyl or an amide protecting group;
R14 is H, C1-C6 alkyl or an amine protecting group;
L is a linker comprising from 1 to about 20 atoms; and
each of m and n is independently an integer from 0 to 2; and
(b) a pharmaceutically acceptable carrier.
The present invention also provides a method for using a compound selected from the group consisting of substituted or unsubstituted benzoic acids; nucleosides and analogs thereof; folic acid and its derivatives; peptides comprising from about 2 to about 10 amino acid residues or derivatives thereof, preferably tripeptides or hexapeptides; macrocyclic compounds containing a ring moiety which comprises from about 8 atoms to about 18 atoms, preferably cyclic peptides or derivatives thereof; and compounds of the above formulas to modulate, e.g., inhibit or enhance, binding of immunoglobulins to Fc receptors in a patient. In a particular embodiment of the present invention, this modulation of Fc receptors by the above identified compounds is used to treat a disease where aggregates of antibodies are produced or where immune complexes are produced by contact of antibody with intrinsic or extrinsic antigen. Modulation of Fc receptors by the above identified compounds can also be used to reduce IgG-mediated tissue damage, to reduce IgE-mediated response and/or to reduce inflammation in a patient.